Synthesis and biological assays of new H-3-antagonists with imidazole and imidazoline polar groups

New histamine H-3-receptor antagonists were synthesised and tested on rat b rain membranes and on electrically stimulated guinea-pig ileum. The new com pounds have a central polar group represented by a 2-alkylimidazole or a 2- thioimidazoline nucleus. The effect of the polar group basicity on the opti mal length of the alkyl chain, connecting this group to a 4(5)-imidazolyl r ing, was investigated. The best affinity values, obtained by displacement o f [H-3]-RAMHA from rat brain, were obtained for the 2-alkylimidazole deriva tives (2a-f) with tetramethylene chain (pK(i) 8.03-8.97), having an interme diate basicity between that of the previously reported 2-thioimidazoles (1a -i) and that of 2-alkylthioimidazolines (3a-h). In contrast, a general lowe ring of affinity (pK(i) 5.90-7.63) was observed for compounds of the last s eries (3a-h), with a complex dependence on the terminal lipophilic group an d chain length. (C) 2000 Elsevier Science S.A. All rights reserved.